1. Mechanism of Anemia of Chronic Disease
Anemia of chronic illness traditionally encompassed any inflammatory, infectious, or malignant disease of
a long-standing nature. The modern definition includesrheumatoid arthritis, severe trauma, heart disease,
or diabetes mellitus. In these conditions, there is primarily a decreased availability of iron, relatively
decreased levels of erythropoietin, and a mild decrease in the lifespan of RBCs to 70-80 days (normally
120 days).[1]
Relatively recently, hepcidin, an endogenous antimicrobial peptide secreted by the liver, has been
identified[2, 3, 4]
as controlling the level of plasma iron by regulating the intestinal absorption of dietary iron,
as well as the release of iron from macrophages and the transfer of iron stored in the hepatocytes.
Increase in hepcidin level in the course of inflammatory disease may be a significant mediator of the
accompanying anemia.[2, 3, 4]
Another proposed mechanism for anemia of chronic illness deals with cytokines, such as interleukins (IL-
1 and IL-6), and tumor necrosis factor (TNF-alpha), which are believed to cause the destruction of RBC
precursors and decrease the number of erythropoietin receptors on progenitor cells.[5, 6, 7]
Whereas hypoxia in the individual with normal functioning kidneys leads to erythropoietin gene
transcription, and hence increased RBC production, in those with anemia of chronic kidney disease, there
is primary deficiency of erythropoietin production by the interstitial fibroblasts, also known as type I
interstitial cells, thereby leading to anemia. The anemia that develops is directly related to the amount of
residual renal function.[8]
The kidneys are responsible for approximately 90% of erythropoietin production
in an individual.
Prevalence of Anemia of Chronic Disease and CKD
In general, anemia is more common in women, in particular, those in their childbearing years. In the latter
decades of life, anemia tends to occur without any particular sex predilection. However, in anemia of
chronic kidney disease, males have a 30% greater risk of developing anemia as compared to their female
counterparts. Although males have higher hemoglobin values, they also have higher rates of advanced
chronic kidney disease. There has been a lower prevalence of anemia in current smokers, which has
been attributed to secondary erythrocytosis.
Anemia is common in patients with chronic kidney disease. The landmark study by Obrador et al showed
that among predialysis patients, 68% of those with advanced chronic kidney disease who required renal
replacement therapy had a hematocrit less than 30 mg/dL; of these, 51% of patients had a hematocrit
less than 28 mg/dL.[9]
Furthermore, although anemia is not as common in earlier stages of chronic kidney
disease, patients with stage III disease have a prevalence of concurrent anemia of 5.2%, whereas those
with stage IV disease have a prevalence of concurrent anemia of 44.1%.[10]
There is also a greater prevalence of anemia of chronic kidney disease in those older than 60 years, as
compared to those aged between 46 and 60 years (seeAnemia in Elderly Persons). This is probably
secondary to the greater rate of chronic kidney disease in older individuals, as well as the lower estimated
glomerular filtration rates (GFRs) that are associated with aging.
Black individuals have not only a 4-fold increased risk of developing chronic kidney disease relative to
white persons[11]
but also an increased prevalence of anemia.
The morbidity and mortality depend greatly on the underlying etiology of the patient's anemia as well as
the stage of the disease, whether early or advanced. In fact, in individuals with advanced stages of
chronic kidney disease, the etiology of anemia tends to be multifactorial (eg, decreased RBC production
due to lack of erythropoietin, increased RBC destruction due to hemolysis [intravascular or extravascular],
as well as increased blood loss due to multiple venipunctures for an array of indications).

2. Evaluation of Anemia and CKD
Symptoms and physical findings
Aside from the obvious concomitant diseases that present with anemia, such as an underlying
malignancy or chronic kidney disease, the symptoms that occur with anemia, listed below, tend to be
quite nonspecific. Nonetheless, clinicians must be wary in that several of these symptoms can be easily
attributed to the state of being elderly and thereby diminishing the value of such symptoms to serve as
alarming signals of disease or pathology.
Generalized weakness or malaise, easy fatigability
Generalized body aches, or myalgias
Orthostatic symptoms (eg, lightheadedness, dizziness)
Syncope or near-syncope
Decreased exercise tolerance
Chest discomfort
Palpitations
Cold intolerance
Sleep disturbances
Inability to concentrate
Loss of appetite
Other causes of normochromic, normocytic anemia and decreased RBC production (hypoproliferative)
should be noted, and conditions involving the bone marrow and secondary conditions involving the liver
and endocrine system should be assessed.
Diseases primarily involving the bone marrow
The following diseases should be included in the differential diagnosis:
Aplastic anemia
Myelophthisic anemia (see the image below) This blood film at 1000X
magnification demonstrates a leukoerythroblastic blood picture with the presence of precursor cells of the myeloid and
erythroid lineage. In addition, anisocytosis, poikilocytosis, and polychromasia can be seen. Courtesy of U. Woermann,
MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Myeloid metaplasia (see the image below) Peripheral smear from a patient
with agnogenic myeloid metaplasia. This image shows the presence of teardrop red blood cells (RBCs) and a
leukoerythroblastic picture with the presence of nucleated RBC precursors and immature myeloid cells. Courtesy of Wei
Wang, MD, and John Lazarchick, MD; Department of Pathology, Medical University of South Carolina.

3. The following conditions should also be evaluated:
Liver disease – Cirrhosis
Endocrine disorders – Hyperthyroidism, hypothyroidism, hypoadrenalism,panhypopituitarism, primary
and secondary hyperparathyroidism
Other causes of normochromic, normocytic anemia and decreased RBC production (hypoproliferative)
should be noted.
The following 4 important laboratory tests are vital in the evaluation of anemia of chronic illness or chronic
kidney disease:
RBC indices
Peripheral blood smear
Reticulocyte count
Bone marrow biopsy (optional in most cases)
Laboratory tests that may help eliminate other common causes of anemia include the following:
Iron panel – serum iron, ferritin, total iron-binding capacity (TIBC), iron saturation (see Role of iron
under Management of Anemia of CKD)
Serum vitamin B12 and folic acid
Serum bilirubin, aspartate aminotransferase (AST), alanine aminotransferase (ALT)
Thyroid stimulating hormone (TSH)
Electrophoretic studies of serum and urine
Serum levels of heavy metals (eg, lead, arsenic)
Reticulocyte count
In the clinical approach to a patient with anemia, aside from reviewing the RBC indices and the peripheral
smear, another important test is the reticulocyte count. A low reticulocyte count usually points to
decreased RBC production as the primary mechanism responsible for anemia, whereas an elevated
reticulocyte count points to increased RBC destruction or hemolysis as the most likely cause.
Although decreased RBC production is the main mechanism in both anemia of chronic illness and anemia
of chronic kidney disease, oftentimes, the anemia is due to a combination of things, including concomitant
blood loss. Therefore, a reticulocyte count should always be interpreted with caution.